tbuckley/cabot-search huggingface dataset:
A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice
Authors: Masayuki Kuraoka, Clare Burn Aschner, Ian W. Windsor, Aakash Mahant Mahant, Scott J. Garforth, Susan Luozheng Kong, Jacqueline M. Achkar, Steven C. Almo, Garnett Kelsoe, Betsy C. Herold
Journal: Journal of Clinical Investigation (2022)

There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2–vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo–electron microscopic structure of the Fab–glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.
Contributions to simplifying the global interpretation of spirometry: high quality spirometry data from Asia
Authors: Arnulf Langhammer
Journal: European Respiratory Journal (2022)

Spirometry is pivotal for the diagnosis, treatment, and follow-up of obstructive lung diseases, and to some extent, might even indicate restrictive lung diseases. Both flow–volume and volume–time curves, as well as absolute values, give important information, but reference values help to interpret whether the results confirm a suspected diagnosis or not. Spirometry is technically a rather complicated manoeuvre requiring a co-operative patient and a skilled technician to ensure acceptability and repeatability criteria are met. Standardised procedures, valid reference values and logical definitions of normality simplify the interpretation of spirometry <https://bit.ly/3SPJv9b>
Compartmentalized regulation of lipid signaling in oxidative stress and inflammation: Plasmalogens, oxidized lipids and ferroptosis as new paradigms of bioactive lipid research
Authors: Alma M. Astudillo, María A. Balboa, Jesús Balsinde
Journal: Progress in Lipid Research (2022)

Perturbations in lipid homeostasis combined with conditions favoring oxidative stress constitute a hallmark of the inflammatory response. In this review we focus on the most recent results concerning lipid signaling in various oxidative stress-mediated responses and inflammation. These include phagocytosis and ferroptosis. The best characterized event, common to these responses, is the synthesis of oxygenated metabolites of arachidonic acid and other polyunsaturated fatty acids. Major developments in this area have highlighted the importance of compartmentalization of the enzymes and lipid substrates in shaping the appropriate response. In parallel, other relevant lipid metabolic pathways are also activated and, until recently, there has been a general lack of knowledge on the enzyme regulation and molecular mechanisms operating in these pathways. Specifically, data accumulated in recent years on the regulation and biological significance of plasmalogens and oxidized phospholipids have expanded our knowledge on the involvement of lipid metabolism in the progression of disease and the return to homeostasis. These recent major developments have helped to establish the concept of membrane phospholipids as cellular repositories for the compartmentalized production of bioactive lipids involved in cellular regulation. Importantly, an enzyme classically described as being involved in regulating the homeostatic turnover of phospholipids, namely the group VIA Ca2+-independent phospholipase A2 (iPLA2β), has taken center stage in oxidative stress and inflammation research owing to its key involvement in regulating metabolic and ferroptotic signals arising from membrane phospholipids. Understanding the role of iPLA2β in ferroptosis and metabolism not only broadens our knowledge of disease but also opens possible new horizons for this enzyme as a target for therapeutic intervention.
The persistence of memory: defining, engineering, and measuring vaccine durability
Authors: Amy C. Palin, Galit Alter, Shane Crotty, Ali H. Ellebedy, M. Chelsea Lane, F. Eun-Hyung Lee, Michela Locci, Angela Malaspina, Conrad Mallia, M. Juliana McElrath, Bali Pulendran, Anjali Singh, M. Patricia D’Souza
Journal: Nature Immunology (2022)
Inhibition of integrated stress response protects against lipid-induced senescence in hypothalamic neural stem cells in adamantinomatous craniopharyngioma
Authors: Chaohu Wang, Huarong Zhang, Jun Fan, Qing Li, Rongrong Guo, Jun Pan, Yawei Liu, Junxiang Peng, Qianchao Zhu, Yiwen Feng, Chengdong Wu, Peng Luo, Xiaoyu Qiu, Jin Shi, Yingying Deng, Songtao Qi, Yi Liu
Journal: Neuro-Oncology (2022)

Adamantinomatous craniopharyngioma (ACP) is a benign tumor with malignant clinical manifestations. ACP adjacent to the hypothalamus often presents with more severe symptoms and higher incidence of hypothalamic dysfunction. However, the mechanism underlying hypothalamic dysfunction remains unclear.Immunostaining was performed to determine the nerve damage to the floor of the third ventricle (3VF) adjacent to ACP and to examine the recruitment and senescence of hypothalamic neural stem cells (htNSCs). The accumulation of lipid droplets (LDs) in htNSCs was evaluated via BODIPY staining, oil red O staining, and transmission electron microscopy. In vitro and in vivo assays were used to evaluate the effect of cystic fluid or oxidized low-density lipoprotein and that of oxytocin (OXT) on htNSC senescence and the hypothalamic function. The protein expression levels were analyzed using western blotting.htNSCs with massive LD accumulation were recruited to the damaged 3VF adjacent to ACP. The LDs in htNSCs induced senescence and reduced neuronal differentiation; however, htNSC senescence was effectively prevented by inhibiting either CD36 or integrated stress response (ISR) signaling. Furthermore, OXT pretreatment reduced lipotoxicity via the inhibition of ISR signaling and the repair of the blood-brain barrier.Reduced LD aggregation or ISR signaling inhibition prevented senescence in htNSCs and identified molecular pathways and potential therapeutic targets that may improve hypothalamic dysfunction in ACP patients.
Electrostatic anti-CD33-antibody–protamine nanocarriers as platform for a targeted treatment of acute myeloid leukemia
Authors: Nicole Bäumer, Annika Scheller, Lisa Wittmann, Andreas Faust, Mara Apel, Subbaiah Chary Nimmagadda, Christiane Geyer, Katharina Grunert, Neele Kellmann, Matthias Peipp, Sareetha Kailayangiri, Matias Ezequiel Gutierrez Suburu, Cristian A. Strassert, Mathias Schenk, Lilo Greune, Christian Rüter, Petra Dersch, Wolfgang Hartmann, Claudia Rossig, Dario Neri, Carsten Müller-Tidow, Christian Schwöppe, Christoph Schliemann, Cyrus Khandanpour, Georg Lenz, Wolfgang E. Berdel, Sebastian Bäumer
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Acute myeloid leukemia (AML) is a fatal clonal hematopoietic malignancy, which results from the accumulation of several genetic aberrations in myeloid progenitor cells, with a worldwide 5-year survival prognosis of about 30%. Therefore, the development of more effective therapeutics with novel mode of action is urgently demanded. One common mutated gene in the AML is the DNA-methyltransferase DNMT3A whose function in the development and maintenance of AML is still unclear. To specifically target “undruggable” oncogenes, we initially invented an RNAi-based targeted therapy option that uses the internalization capacity of a colorectal cancer specific anti-EGFR-antibody bound to cationic protamine and the anionic siRNA. Here, we present a new experimental platform technology of molecular oncogene targeting in AML. Methods Our AML-targeting system consists of an internalizing anti-CD33-antibody–protamine conjugate, which together with anionic molecules such as siRNA or ibrutinib-Cy3.5 and cationic free protamine spontaneously assembles into vesicular nanocarriers in aqueous solution. These nanocarriers were analyzed concerning their physical properties and relevant characteristics in vitro in cell lines and in vivo in xenograft tumor models and patient-derived xenograft leukemia models with the aim to prepare them for translation into clinical application. Results The nanocarriers formed depend on a balanced electrostatic combination of the positively charged cationic protamine-conjugated anti-CD33 antibody, unbound cationic protamine and the anionic cargo. This nanocarrier transports its cargo safely into the AML target cells and has therapeutic activity against AML in vitro and in vivo. siRNAs directed specifically against two common mutated genes in the AML, the DNA-methyltransferase DNMT3A and FLT3-ITD lead to a reduction of clonal growth in vitro in AML cell lines and inhibit tumor growth in vivo in xenotransplanted cell lines. Moreover, oncogene knockdown of DNMT3A leads to increased survival of mice carrying leukemia patient-derived xenografts. Furthermore, an anionic derivative of the approved Bruton’s kinase (BTK) inhibitor ibrutinib, ibrutinib-Cy3.5, is also transported by this nanocarrier into AML cells and decreases colony formation. Conclusions We report important results toward innovative personalized, targeted treatment options via electrostatic nanocarrier therapy in AML.
Update in the treatment of non-melanoma skin cancers: the use of PD-1 inhibitors in basal cell carcinoma and cutaneous squamous-cell carcinoma
Authors: Paolo A Ascierto, Dirk Schadendorf
Journal: Journal for ImmunoTherapy of Cancer (2022)

Non-melanoma skin cancer (NMSC) includes a wide range of cutaneous tumors, the most frequent of which are basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC). Although NMSC is usually cured by surgical resection, in rare cases it can progress to locally advanced and metastatic disease. Risk factors for advanced disease include comorbidities, neglect, and immunosuppression. Advanced NMSC may require systemic treatment if surgery and radiation are not feasible. Chemotherapy, epidermal growth factor receptor (EGFR) inhibitors in CSCC, and hedgehog inhibitors in BCC have been used but are generally of limited benefit, with responses often short-lived and toxicity issues. Given the high mutational burden of NMSC, the use of immunotherapy has been investigated and two anti-PD-1 antibodies, cemiplimab and pembrolizumab, are approved for the treatment of advanced CSCC not curable by surgery or radiation. Both have shown durable responses with good tolerability in patients in phase II trials and anti-PD-1 therapy is now the standard of care for locally advanced and metastatic CSCC. PD-1 blockade is also approved as second-line therapy in advanced BCC, with frequent and durable responses after failure on hedgehog inhibitor therapy. PD-1 checkpoint inhibition is being assessed for NMSC in combination with other modalities, including oncolytic viruses and EGFR inhibitors. Adjuvant and neoadjuvant use of cemiplimab and pembrolizumab is also being investigated with several ongoing trials. Further clinical trials of immunotherapy must be prioritized in NMSC for further improvement in outcomes.
Upadacitinib Therapy Reduces Ulcerative Colitis Symptoms as Early as Day 1 of Induction Treatment
Authors: Edward V. Loftus, Jean-Frederic Colombel, Ken Takeuchi, Xiang Gao, Remo Panaccione, Silvio Danese, Marla Dubinsky, Stefan Schreiber, Dapo Ilo, Tricia Finney-Hayward, Wen Zhou, Charles Phillips, Yuri Sanchez Gonzalez, Lei Shu, Xuan Yao, Qing Zhou, Séverine Vermeire
Journal: Clinical Gastroenterology and Hepatology (2022)
High-protein diet prevents fat mass increase after dieting by counteracting Lactobacillus-enhanced lipid absorption
Authors: Wuling Zhong, Hui Wang, Yale Yang, Yali Zhang, Hejin Lai, Yalan Cheng, Huimin Yu, Ning Feng, Rui Huang, Shen Liu, Sheng Yang, Tongyang Hao, Baoyu Zhang, Hao Ying, Fang Zhang, Feifan Guo, Qiwei Zhai
Journal: Nature Metabolism (2022)
Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan and responses to rapamycin
Authors: Jennifer C. Regan, Yu-Xuan Lu, Enric Ureña, Ralf L. Meilenbrock, James H. Catterson, Disna Kißler, Jenny Fröhlich, Emilie Funk, Linda Partridge
Journal: Nature Aging (2022)

Abstract Pharmacological attenuation of mTOR presents a promising route for delay of age-related disease. Here we show that treatment of Drosophila with the mTOR inhibitor rapamycin extends lifespan in females, but not in males. Female-specific, age-related gut pathology is markedly slowed by rapamycin treatment, mediated by increased autophagy. Treatment increases enterocyte autophagy in females, via the H3/H4 histone-Bchs axis, whereas males show high basal levels of enterocyte autophagy that are not increased by rapamycin feeding. Enterocyte sexual identity, determined by transformer Female expression, dictates sexually dimorphic cell size, H3/H4- Bchs expression, basal rates of autophagy, fecundity, intestinal homeostasis and lifespan extension in response to rapamycin. Dimorphism in autophagy is conserved in mice, where intestine, brown adipose tissue and muscle exhibit sex differences in autophagy and response to rapamycin. This study highlights tissue sex as a determining factor in the regulation of metabolic processes by mTOR and the efficacy of mTOR-targeted, anti-aging drug treatments.
Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity
Authors: Jonathan J. Park, Adan Codina, Lupeng Ye, Stanley Lam, Jianjian Guo, Paul Clark, Xiaoyu Zhou, Lei Peng, Sidi Chen
Journal: Journal of Hematology & Oncology (2022)

Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings.
HIV Services and Outcomes During the COVID-19 Pandemic — United States, 2019–2021
Authors: Karen W. Hoover, Weiming Zhu, Zanetta C. Gant, Kevin P. Delaney, Jeffrey Wiener, Neal Carnes, Dominique Thomas, John Weiser, Ya-Lin A. Huang, Laura W. Cheever, Athena P. Kourtis
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Increasing HIV testing, preexposure prophylaxis (PrEP), and antiretroviral therapy (ART) are pillars of the federal Ending the HIV Epidemic in the U.S. (EHE) initiative, with a goal of decreasing new HIV infections by 90% by 2030.* In response to the COVID-19 pandemic, a national emergency was declared in the United States on March 13, 2020, resulting in the closure of nonessential businesses and most nonemergency health care venues; stay-at-home orders also limited movement within communities (1). As unemployment increased during the pandemic (2), many persons lost employer-sponsored health insurance (3). HIV testing and PrEP prescriptions declined early in the COVID-19 pandemic (4-6); however, the full impact of the pandemic on use of HIV prevention and care services and HIV outcomes is not known. To assess changes in these measures during 2019-2021, quarterly data from two large U.S. commercial laboratories, the IQVIA Real World Data - Longitudinal Prescription Database (IQVIA),† and the National HIV Surveillance System (NHSS)§ were analyzed. During quarter 1 (Q1)¶ 2020, a total of 2,471,614 HIV tests were performed, 190,955 persons were prescribed PrEP, and 8,438 persons received a diagnosis of HIV infection. Decreases were observed during quarter 2 (Q2), with 1,682,578 HIV tests performed (32% decrease), 179,280 persons prescribed PrEP (6% decrease), and 6,228 persons receiving an HIV diagnosis (26% decrease). Partial rebounds were observed during quarter 3 (Q3), with 2,325,554 HIV tests performed, 184,320 persons prescribed PrEP, and 7,905 persons receiving an HIV diagnosis. The proportion of persons linked to HIV care, the number who were prescribed ART, and proportion with a suppressed viral load test (<200 copies of HIV RNA per mL) among those tested were stable during the study period. During public health emergencies, delivery of HIV services outside of traditional clinical settings or that use nonclinical delivery models are needed to facilitate access to HIV testing, ART, and PrEP, as well as to support adherence to ART and PrEP medications.
SARS-CoV-2 Serology and Self-Reported Infection Among Adults — National Health and Nutrition Examination Survey, United States, August 2021–May 2022
Authors: Lara J. Akinbami, Deanna Kruszon-Moran, Chia-Yih Wang, Renee J. Storandt, Jason Clark, Minsun K. Riddles, Leyla K. Mohadjer
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

CDC COVID-19 surveillance systems monitor SARS-CoV-2 antibody prevalence to collect information about asymptomatic, undiagnosed, and unreported disease using national convenience samples of blood donor data from commercial laboratories (1,2). However, nonrandom sampling of data from these systems could affect prevalence estimates (1-3). The National Health and Nutrition Examination Survey (NHANES) collects SARS-CoV-2 serology data among a sample of the general U.S. civilian population (4). In addition, NHANES collects self-reported COVID-19 vaccination and disease history, and its statistical sampling design is not based on health care access or blood donation. Therefore, NHANES data can be used to better quantify asymptomatic SARS-CoV-2 infection prevalence and seropositivity attained through infection without vaccination. Preliminary NHANES 2021-2022 results indicated that 41.6% of adults aged ≥18 years had serology indicative of past infection and that 43.7% of these adults, including 57.1% of non-Hispanic Black or African American (Black) adults, reported never having had COVID-19, possibly representing asymptomatic infection. In addition, 25.5% of adults whose serology indicated past infection reported never having received COVID-19 vaccination. Prevalences of seropositivity in the absence of vaccination were higher among younger adults and Black adults, reflecting the lower observed vaccination rates among these groups (5). These findings raise health equity concerns given the disparities observed in SARS-CoV-2 infection and COVID-19 vaccination. Results from NHANES 2021-2022 can guide ongoing efforts to achieve vaccine equity in COVID-19 primary vaccination series and booster dose coverage.
<i>Erratum:</i> Vol. 71, No. 42
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

the case report of patient E should have included a citation to a previously published case report that described the first 2 days of patient E's clinical course.On p. 1346, the last two sentences under the heading "Patient E" should have read "Neither tecovirimat nor trifluridine was immediately available; the patient was treated with naproxen.Her ocular symptoms improved, and she was discharged after 3 days with a 14-day course of oral tecovirimat and a 5-day course of topical trifluridine (2).In the figure on p. 1344 (Figure 1), the timeline of treatment administration for patient E should have indicated 5 days of treatment with trifluridine.In addition, on p. 1347, the list of references should have included the following: "2.
Physical Activity and Risk of Major Diabetes-Related Complications in Individuals With Diabetes: A Systematic Review and Meta-Analysis of Observational Studies
Authors: Marlene Rietz, Alexander Lehr, Eriselda Mino, Alexander Lang, Edyta Szczerba, Tim Schiemann, Christian Herder, Nina Saatmann, Wolfgang Geidl, Janett Barbaresko, Manuela Neuenschwander, Sabrina Schlesinger
Journal: Diabetes Care (2022)

BACKGROUND Physical activity is a cornerstone in diabetes management; however, evidence synthesis on the association between physical activity and long-term diabetes-related complications is scarce. PURPOSE To summarize and evaluate findings on physical activity and diabetes-related complications, we conducted a systematic review and meta-analysis. DATA SOURCES We searched PubMed, Web of Science, and the Cochrane Library for articles published up to 6 July 2021. STUDY SELECTION We included prospective studies investigating the association between physical activity and incidence of and mortality from diabetes-related complications, i.e., cardiovascular disease (CVD), coronary heart disease, cerebrovascular events, heart failure, major adverse cardiovascular events, and microvascular complications such as retinopathy and nephropathy, in individuals with diabetes. DATA EXTRACTION Study characteristics and risk ratios with 95% CIs were extracted. Random-effects meta-analyses were performed, and the certainty of evidence and risk of bias were evaluated with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tools. DATA SYNTHESIS Overall, 31 studies were included. There was moderate certainty of evidence that high versus low levels of physical activity were inversely associated with CVD incidence, CVD mortality (summary risk ratio 0.84 [95% CI 0.77, 0.92], n = 7, and 0.62 [0.55, 0.69], n = 11), and microvascular complications (0.76 [0.67, 0.86], n = 8). Dose-response meta-analyses showed that physical activity was associated with lower risk of diabetes-related complications even at lower levels. For other outcomes, similar associations were observed but certainty of evidence was low or very low. LIMITATIONS Limitations include residual confounding and misclassification of exposure. CONCLUSIONS Physical activity, even below recommended amounts, was associated with reduced incidence of diabetes-related complications.